Co-resistance necessitating use of less effective or relatively toxic reserve antibiotics (aminoglycosides, tigecycline and colistin/polymyxin B) may worsen survival. We investigated difficult-to-treat resistance (DTR) in gram-negative bloodstream infections (GNBSIs) defined by absence of susceptibility to all first-line agents (carbapenems, beta-lactams and fluoroquinolones (FQ) using a large clinical database of US hospitals. We found that survival in antimicrobial-resistant GNBSI is highly contingent on presence of active first-line option(s); DTR limits treatment options to reserve agents, including aminoglycosides, which are far from universally active. DTR remained infrequent (1%) among GNBSI, but occurred at half of the hospitals examined and across all US regions. This work has been presented at the Annual Meetings of the Infectious Diseases Society of America, in New Orleans, LA in October 2016 and Society of Critical Care Medicine, in San Antonio, TX in February 2018. A manuscript on this work has been published in Clinical Infectious Diseases. As a next step, we plan to validate our findings using the Cerner Healthfacts repository of electronic health records, and study the landscape of emerging antibiotics to understand their real-world use and demand. We also intend to determine whether shorter courses of therapy are sufficient in clinically suspected serious infection when no pathogens are identified, as a move to promote stewardship.